PVS1_VeryStrong is met: c.198C>A (p.Tyr66Ter) is a nonsense variant introducing a premature termination codon at codon 66, which is ≤ codon 891 in MSH2, satisfying the InSiGHT MSH2 v2.0.0 VCEP PVS1 rule for full-strength PVS1.¹ PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,601,554 alleles) and gnomAD v2.1, satisfying the VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles).² Under the InSiGHT MSH2 v2.0.0 VCEP combination rules (Richards et al. 2015 framework), the combination of 1 Pathogenic Very Strong (PVS1) and 1 Pathogenic Supporting (PM2) does not satisfy any rule for Pathogenic or Likely Pathogenic classification. A minimum of 1 Very Strong + 2 Supporting, or 1 Very Strong + 1 Moderate would be required for Pathogenic or Likely Pathogenic, respectively. The variant is classified as Variant of Uncertain Significance (VUS) per the VCEP combination rule set.³ This variant has been reported as Pathogenic by 6 clinical laboratories in ClinVar (VariationID: 645593). However, the VCEP does not recognize PP5/ClinVar consensus as an applicable criterion, and no expert panel classification has been issued for this variant.⁴ No variant-specific functional (PS3/BS3), segregation (PP1/BS4), tumor phenotype (PP4/BP5), or de novo (PS2) data were identified for this variant in any reviewed source. Full-text publications retrieved for relevant PMIDs (24362816, 10946232, 11257106, 15528792, 23391514) did not contain accessible article content — all returned Sci-Hub landing page artifacts without variant-specific evidence.